Bisphosphonates are commonly used for the
prevention and treatment of osteoporosis as well as other conditions affecting
bone (eg, Paget's disease).1 The use of these agents is associated with
gastrointestinal adverse effects including: abdominal pain, flatulence,
indigestion, and, more seriously, ulceration, erosion, and perforation of the
esophagus.1 In the 1990s, close to 500,000 prescriptions for
alendronate were written world-wide with approximately 200 reported esophageal
adverse drug reactions.2 Of the 200 reported events, greater than half
were associated with improper medication administration which suggests a
misrepresentation of true occurrence.2 The overall incidence of severe
esophageal complications with bisphosphonate use is 1 to 2%.1,2 Although
case reports and endoscopic studies have linked bisphosphonate use with
esophageal ulcerations, large controlled clinical trials have not shown a significant
difference compared to placebo.3
Phospholipids
line the luminal side of the gastrointestinal (GI) tract and have both a
positive and negative charge (zwitterionic in nature). The zwitterionic
alignment of phospholipids creates a protective hydrophobic barrier between the
epithelial lining and the acidic environment in the lumen of the GI
tract. When positively charged hydrogen molecules come into contact with
the phospholipid bilayer, the hydrogen molecules are unable to penetrate
through the bilayer, given the hydrophobic environment. In other words,
the hydrophobic properties of the phospholipids prevent gastric acid from
reaching the epithelium. Bisphosphonates act as topical irritants to the
GI lining resulting in chemical esophagitis.4 It is hypothesized that
bisphosphonates compromise the protective, hydrophobic mucosal barrier of the
GI tract allowing gastric acid to agitate the epithelial lining. The
chronic irritation and inflammation leads to erosions and/or ulcerations.
Phosphatidylcholine (PC) is one of the phospholipids responsible for the
hydrophobic properties of the bilayer. Phosphatidylcholine has
demonstrated an ability to create a protective environment on both inert and
biological surfaces and protect GI cells from irritating agents. Both
bisphosphonates and PC are similar in size and molecular structures - with a
negatively charged phosphate group and a positively charged nitrogen group
connected by a 2-carbon chain. The comparable molecular composition of
bisphosphonates and zwitterionic phospholipids creates competitive binding on
the mucosal layer. When bisphosphonates bind, this prevents PC or other
protective phospholipids from binding and producing the hydrophobic barrier
that protects the epithelial lining from gastric acid.5
The
reduction in PC and hydrophobicity theory has been examined in the animal
population with rodents.1 When bisphosphonates were administered without
other GI-irritating drugs, little to no gastrointestinal irritation was found,
but when bisphosphonates were given concomitantly with indomethacin, gastric
lesions occurred.1
With
the knowledge of potential topical gastrointestinal irritation with
bisphosphonate use, patients should be educated on proper administration to prevent
esophageal complications. 1 All agents in this drug class should be taken
with a full glass of water to ensure medication does not lodge in the
esophagus. Additionally, patients must remain in an upright position for
at least 30 minutes after administration to prevent reflux into the esophagus
that can occur when in a supine position. The instruction to take
bisphosphonates on an empty stomach does not relate to esophageal irritation,
but instead allows for greater medication absorption.
It
is reported that the incidence of esophageal irritation associated with
bisphosphonates increases with age, is more common in the female patient
population, and is associated with patients who have history of
gastrointestinal problems or are concomitantly taking medications that are also
gastrointestinal irritants medications (e.g., NSAIDs).1 True associations
can most likely be linked to a diagnosis of a gastrointestinal disease or use
of irritant medications, but the connection seen with female population and
increase in age is most likely reflective of the patient population mostly
affected by osteoporosis.1
References:
- Cryer
B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract
problems: what is the evidence? Mayo Clin Proc 2002;77:1031-1043.
- de
Groen PC, Lubbe DF, Hirsch LJ et al. Esophagitis associated with the use
of alendronate. N Engl J Med 1996;335(14):1016-21.
- Bauer
DC, Black D, Ensrud K et al. Upper gastrointestinal tract safety profile
of alendronate - the fracture intervention trail. Arch Intern Med 2000;160:517-525.
- Lichtenberger LM, Romero JJ, Bigson
GW et al. Effect of bisphosphonates on surface hydrophobicity and
phosphatidylcholine concentration of rodent gastric mucosa. Dig Dis and
Sci 2000;45(9):1792-1801.
